Structure–activity studies on the inhibition of γ-aminobutyric acid uptake in brain slices by compounds related to nipecotic acid

1979 ◽  
Vol 57 (6) ◽  
pp. 581-585 ◽  
Author(s):  
J. D. Wood ◽  
D. Tsui ◽  
J. W. Phillis
Keyword(s):  
Cortical Neurons ◽  
Therapeutic Potential ◽  
Brain Slices ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Nipecotic Acid ◽  
Depressant Action ◽  
Methyl Derivatives ◽  
Derivatives Of

Various N-methyl derivatives of nipecotic acid and related compounds were tested as inhibitors of γ-aminobutyric acid (GABA) uptake into mini slices. N-Methylnipecotic acid, N,N-dimethyinipecotic acid, N-methylguvacine, and N-methylnicotinic acid were effective inhibitors. None of them, however, were as potent as nipecotic acid itself. All the effective inhibitors, including nipecotic acid, also inhibited the uptake of L-proline, but to a much lesser extent. Four of the test compounds produced a depressant action on cerebral cortical neurons, but even N-methylisoguvacine, the most potent in this respect, was considerably less active than GABA. None of the test compounds caused any clearly discernible changes in the gross behaviour or appearance of mice in the 1-h period following intramuscular injection. It was concluded that methylation of the N atom of nipecotic acid and its derivatives was unlikely to lead to the development of agents with greater experimental or therapeutic potential than that of nipecotic acid itself, if the action of the agent was dependent on its effects on GABA uptake.

Systemic CI-966, a new γ-aminobutyric acid uptake blocker, enhances γ-aminobutyric acid action in CA1 pyramidal layer in situ

1990 ◽  
Vol 68 (9) ◽  
pp. 1194-1199 ◽  
Author(s):  
U. Ebert ◽  
K. Krnjević
Keyword(s):  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Sprague Dawley ◽  
Nipecotic Acid ◽  
Ca1 Region ◽  
Stratum Pyramidale ◽  
Sprague Dawley Rats ◽  
Pyramidal Layer ◽  
Urethane Anaesthesia

A new potent, blood–brain barrier permeable γ-aminobutyric acid (GABA) uptake blocker, 1-[2-[bis[4-(trifluoromethyl)-phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (CI-966) was administered systemically by i.p. injection (5 mg/kg) in Sprague–Dawley rats under urethane anaesthesia. Twenty to thirty minutes after injection there was a highly variable, but overall significant, enhancement of the inhibition of hippocampal population spikes by GABA applied by microiontophoresis in the CA1 region. Like the effect of nipecotic acid (applied locally by iontophoresis), the potentiation by CI-966 was clearest when GABA was applied in or near the stratum pyramidale where its action normally is weakest and shows the most pronounced fading. This change in GABA potency is most simply explained by a reduction in GABA uptake.Key words: GABA, muscimol, nipecotic acid, GABA-uptake blocker, epilepsy.

scholarly journals Concurrent acetylcholinesterase staining and gamma-aminobutyric acid uptake of cortical neurons in culture.

1981 ◽  
Vol 29 (2) ◽  
pp. 306-308 ◽  
Author(s):  
M M Mesulam ◽  
M Dichter
Keyword(s):  
Tissue Culture ◽  
Cortical Neurons ◽  
Gabaergic Neurons ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Gamma Aminobutyric Acid ◽  
Acetylcholinesterase Staining ◽  
Culture Positive

Gamma-aminobutyric acid (GABA) uptake and acetylcholinesterase (AChE) content were demonstrated concurrently in cortical neurons grown in tissue culture. Positive reactions either for GABA uptake or for AChE content were encountered in pyramidal and stellate, as well as spindle-shaped neurons. Neither reaction was confined to a specific morphological subtype. Nearly half the neurons were negative for either reaction. Most of the remaining neurons were positive only for GABA or only for AChE. However, a subpopulation of neurons showed not only a high AChE content, but also an avid GABA uptake. Thus, four types of neurons could be identified on the basis of these two reactions. The high AChE content in some of the cortical neurons that also showed GABA uptake indicates that there are at least two distinct types of GABAergic neurons.

scholarly journals Design, Synthesis and Enhanced BBB Penetration Studies of L-serine-Tethered Nipecotic Acid-Prodrug

Drug Research ◽  
2020 ◽  
Author(s):  
Meenakshi Dhanawat ◽  
Sumeet Gupta ◽  
Dinesh Kumar Mehta ◽  
Rina Das
Keyword(s):  
Epileptic Activity ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Nipecotic Acid ◽  
Design Synthesis ◽  
Hydrophilic Nature ◽  
Carrier Mediated Transport ◽  
Ester Prodrug ◽  
Hplc Data

Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial-aminobutyric acid (GABA) uptake in vitro. Due to its hydrophilic nature, nipecotic acid does not readily cross the blood-brain barrier (BBB). Large neutral amino acids (LAT1)-knotted nipecotic acid prodrug was designed and synthesized with the aim to enhance the BBB permeation by the use of carrier-mediated transport. The synthesized prodrug was tested in animal models of Pentylenetetrazole (PTZ)-induced convulsions in mice. Further pain studies were carried out followed by neurotoxicity estimation by writhing and rota-rod test respectively. HPLC data suggests that the synthesized prodrug has improved penetration through BBB. Nipecotic acid-L-serine ester prodrug with considerable anti-epileptic activity, and the ability to permeate the BBB has been successfully synthesized. Graphical Abstract.

scholarly journals Identification and Characterization of γ-Aminobutyric Acid Uptake System GabPCg(NCgl0464) in Corynebacterium glutamicum

2012 ◽  
Vol 78 (8) ◽  
pp. 2596-2601 ◽  
Author(s):  
Zhi Zhao ◽  
Jiu-Yuan Ding ◽  
Wen-hua Ma ◽  
Ning-Yi Zhou ◽  
Shuang-Jiang Liu
Keyword(s):  
Amino Acid ◽  
Corynebacterium Glutamicum ◽  
Dry Weight ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Uptake System ◽  
Content Type ◽  
Gaba Transporters ◽  
New Type

ABSTRACTCorynebacterium glutamicumis widely used for industrial production of various amino acids and vitamins, and there is growing interest in engineering this bacterium for more commercial bioproducts such as γ-aminobutyric acid (GABA). In this study, aC. glutamicumGABA-specific transporter (GabPCg) encoded byncgl0464was identified and characterized. GabPCgplays a major role in GABA uptake and is essential toC. glutamicumgrowing on GABA. GABA uptake by GabPCgwas weakly competed byl-Asn andl-Gln and stimulated by sodium ion (Na+). TheKmandVmaxvalues were determined to be 41.1 ± 4.5 μM and 36.8 ± 2.6 nmol min−1(mg dry weight [DW])−1, respectively, at pH 6.5 and 34.2 ± 1.1 μM and 67.3 ± 1.0 nmol min−1(mg DW)−1, respectively, at pH 7.5. GabPCghas 29% amino acid sequence identity to a previously and functionally identified aromatic amino acid transporter (TyrP) ofEscherichia colibut low identities to the currently known GABA transporters (17% and 15% toE. coliGabP andBacillus subtilisGabP, respectively). The mutant RES167 Δncgl0464/pGXKZ9 with the GabPCgdeletion showed 12.5% higher productivity of GABA than RES167/pGXKZ9. It is concluded that GabPCgrepresents a new type of GABA transporter and is potentially important for engineering GABA-producingC. glutamicumstrains.

Synthesis of Novel GABA Uptake Inhibitors. 3. Diaryloxime and Diarylvinyl Ether Derivatives of Nipecotic Acid and Guvacine as Anticonvulsant Agents1

1999 ◽  
Vol 42 (18) ◽  
pp. 3447-3462 ◽  
Author(s):  
Lars J. S. Knutsen ◽  
Knud Erik Andersen ◽  
Jesper Lau ◽  
Behrend F. Lundt ◽  
Rodger F. Henry ◽  
...  
Keyword(s):  
Gaba Uptake ◽  
Nipecotic Acid ◽  
Uptake Inhibitors ◽  
Derivatives Of ◽  
Gaba Uptake Inhibitors

scholarly journals Inhibition of high-affinity gamma-aminobutyric acid uptake in primary astrocyte cultures by phorbol esters and phospholipase C

1991 ◽  
Vol 275 (2) ◽  
pp. 435-439 ◽  
Author(s):  
J Gomeza ◽  
M Casado ◽  
C Gimenez ◽  
C Aragon
Keyword(s):  
Phospholipase C ◽  
Glial Cells ◽  
Kinase Inhibitor ◽  
Primary Cultures ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Acid Uptake ◽  
Gamma Aminobutyric Acid ◽  
Gaba Transport ◽  
High Affinity

The effects of phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), on high-affinity Na(+)-dependent gamma-aminobutyric acid (GABA) uptake were investigated in primary cultures of neurons and glial cells from rat brain cortex. Incubation of glial cells with PMA led to concentration- and time-dependent decreases in the GABA transport in glial cells. This effect could be completely suppressed by addition of the PKC inhibitor H7. The PMA effects could be mimicked by oleoylacetylglycerol, the diacylglycerol kinase inhibitor R59022 and exogenous phospholipase C. Treatment with PMA did not affect GABA transport in neuronal cells.

γ-Aminobutyric Acid Uptake Inhibition and Anticonvulsant Activity of Nipecotic Acid Esters

1984 ◽  
Vol 73 (11) ◽  
pp. 1612-1616 ◽  
Author(s):  
A. Michael Crider ◽  
J.D. Wood ◽  
Kathryn D. Tschappat ◽  
Christine N. Hinko ◽  
Karen Seibert
Keyword(s):  
Anticonvulsant Activity ◽  
Aminobutyric Acid ◽  
Acid Uptake ◽  
Nipecotic Acid ◽  
Uptake Inhibition ◽  
Acid Esters

Nipecotic acid and 2,4-diaminobutyric acid enhance the actions of muscimol on cerebral cortical neurons

1978 ◽  
Vol 56 (3) ◽  
pp. 443-446 ◽  
Author(s):  
G. G. Yarbrough
Keyword(s):  
New York ◽  
Nervous System ◽  
Amino Acid ◽  
Cortical Neurons ◽  
Gaba Uptake ◽  
Nipecotic Acid ◽  
Diaminobutyric Acid ◽  
Selective Blockade ◽  
High Affinity ◽  
Cerebral Cortical Neurons

Iontophoretically applied muscimol exerted a potent inhibitory action on the firing of spontaneously active cerebral cortical neurons of rats. On the basis of ejection currents employed, muscimol was considerably more potent than γ-aminobutyric acid (GABA), and the inhibitions produced by muscimol were frequently of a longer duration than those observed with GABA. Nipecotic acid and diaminobutyric acid (DABA) are potent inhibitors of high-affinity GABA uptake systems and muscimol is not thought to be a substrate for high-affinity GABA uptake (JOHNSTON, G. A. R. 1976. Physiolic pharmacology of GABA and its antagonists in the vertebrate nervous system. In GABA in nervous system function. Edited by E. Roberts, T. Chase, and D. B. Tower. Raven Press, New York). However, nipecotic acid and DABA consistently enhanced the inhibitory effects of both GABA and muscimol on cortical neurons while not affecting monoamine or adenosine 5′-monophosphate induced inhibitions. These findings suggest that iontophoretically applied nipecotic acid and DABA have some specificity for amino acid mechanisms in the cortex, but their actions appear to be more complex than can be explained by a selective blockade of GABA uptake processes. Thus, the uptake blockers may be exerting a weak and not readily detectable agonist action at amino acid receptors. Alternatively, the actions of iontophoretically applied muscimol may be partially terminated by uptake through GABA uptake systems.

scholarly journals Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin

2011 ◽  
Vol 192 (1) ◽  
pp. 153-169 ◽  
Author(s):  
Maxim M. Bespalov ◽  
Yulia A. Sidorova ◽  
Sarka Tumova ◽  
Anni Ahonen-Bishopp ◽  
Ana Cathia Magalhães ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Receptor Tyrosine Kinase ◽  
Cortical Neurons ◽  
Dopaminergic Neurons ◽  
Therapeutic Potential ◽  
Aminobutyric Acid ◽  
Dependent Manner ◽  
Kinase Activation ◽  
Matrix Bound ◽  
Immobilized Matrix

Glial cell line–derived neurotrophic factor (GDNF) family ligands (GFLs) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson’s disease. Soluble GFLs bind to a ligand-specific glycosylphosphatidylinositol-anchored coreceptor (GDNF family receptor α) and signal through the receptor tyrosine kinase RET. In this paper, we show that all immobilized matrix-bound GFLs, except persephin, use a fundamentally different receptor. They interact with syndecan-3, a transmembrane heparan sulfate (HS) proteoglycan, by binding to its HS chains with high affinity. GFL–syndecan-3 interaction mediates both cell spreading and neurite outgrowth with the involvement of Src kinase activation. GDNF promotes migration of cortical neurons in a syndecan-3–dependent manner, and in agreement, mice lacking syndecan-3 or GDNF have a reduced number of cortical γ-aminobutyric acid–releasing neurons, suggesting a central role for the two molecules in cortical development. Collectively, syndecan-3 may directly transduce GFL signals or serve as a coreceptor, presenting GFLs to the signaling receptor RET.

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